Of Interest
Abbvie dual combination Glecaprevir /Pibrentasvir
Gilead fixed dose combination SOF/VEL/VOX
Merck fixed-dose combination tablet MK3 (MK-3682/grazoprevir/ruzasvir)
Therap Adv Gastroenterol. 2017 Feb; 10(2): 277–282.
Published online 2017 Jan 25. doi: 10.1177/1756283X16683875
This update reviews some upcoming therapies for the treatment of chronic hepatitis C
See table 1 below for; Direct-acting combination antiviral therapies expected to be approved in 2017
Novel emerging treatments for hepatitis C infection: a fast-moving pipeline
Ara A. Kardashian and Paul J. PockrosThis update reviews some upcoming therapies for the treatment of chronic hepatitis C
See table 1 below for; Direct-acting combination antiviral therapies expected to be approved in 2017
Novel emerging treatments for hepatitis C infection: a fast-moving pipeline
Abstract
Advances in the treatment of chronic hepatitis C has been one of the pinnacles of medical science in the last 25 years. The age of direct-acting antivirals (DAAs) has led to cure rates >95% with shorter duration and low toxicity regimens, thus changing the landscape of the era of pegylated interferon and ribavirin (RBV). However, there remain some challenges with these therapies as there are multiple regimens available with a fair amount of sophistication required to administer them. Treatment continues to require knowledge of prior treatment status, viral genotype and fibrosis assessment, thus affording an opportunity for improvement in future regimens. This update reviews some upcoming therapies for the treatment of chronic hepatitis C.
Keywords: direct-acting antivirals, emerging treatments, hepatitis C
Introduction
Direct-acting antivirals (DAAs) target viral proteins of the hepatitis C virus (HCV) which are critical for viral replication, resulting in the four classes of antivirals currently approved: nonstructural protein 3 (NS3) protease inhibitors (PI), NS5A inhibitors, NS5b nucleot(s)ide polymerase inhibitors and NS5b non-nucleot(s)ide polymerase inhibitors. It is unlikely that drugs will be developed outside of these classes, other than recent efforts with microRNA-122. Instead, we will see improvements upon the current drugs with second generation compounds. There remain unmet needs for treatment in some patients such as those who have failed NS5A regimens, those who have developed resistance-associated substitutions (RASs) and those who have pre-existing RASs that confer resistance. Other opportunities for improvement include pangenotypic regimens, eliminating the need for ribavirin (RBV), reducing duration of therapy, and reducing the cost of therapy. This review will address novel therapies currently in late phase studies.
Current treatment options
Currently, treatment options are organized by genotype, presence or absence of cirrhosis, and treatment experience. The following is a brief overview of available regimens and their indications, not an indepth review.
Treatment-naïve patients
For genotype 1, treatment options include daily fixed-dose combinations of elbasvir/grazoprevir, ledipasvir/sofosbuvir, paritaprevir/ritonavir/ombitasvir with dasabuvir and RBV, sofosbuvir/velpatasvir, as well as simeprevir plus sofosbuvir, and daclatasvir plus sofosbuvir. Variations in the regimen are based on genotype (1a versus 1b), presence or absence of compensated cirrhosis, and presence of pretreatment RASs. Currently, only one regimen requires pretreatment determination of the presence of NS5A RASs (elbasvir/grazoprevir). If an RAS is present at positions M28, Q30, L31 or Y93, then the patient requires 16 rather than 12 weeks of treatment with the addition of RBV.1 The details of all these regimens are available in the current American Association for the Study of Liver Diseases (AASLD)/ Infectious Diseases Society of America (IDSA) Guideline document.2
For genotypes 2 and 3, sofosbuvir/velpatasvir and daclatasvir plus sofosbuvir are available. Again, duration can vary based on presence of cirrhosis and RBV is required in some patients with genotype 3 HCV infection. Genotype 4 regimens include 12 weeks of daily fixed-dose combinations of paritaprevir/ritonavir/ombitasvir with RBV, sofosbuvir/velpatasvir, elbasvir/grazoprevir, and ledipasvir/sofosbuvir.2 Additionally, in the European Association for the Study of the Liver (EASL) guidelines, sofosbuvir/simeprevir and sofosbuvir/daclatasvir are indicated.3 Treatment-naïve genotype 5 and 6 HCV options are daily fixed-dose combinations of sofosbuvir/velpatasvir or ledipasvir/sofosbuvir, both for 12 weeks for those without cirrhosis or with compensated cirrhosis2,3 and sofosbuvir/daclatasvir for 12 weeks.3
Treatment-experienced patients
Options for those having failed prior therapy depends on what was previously used and presence of RASs in addition to the same factors stated previously (genotype, presence or absence of cirrhosis). In general, the same options are available if the prior treatment was with pegylated interferon (PEG-IFN) and RBV. This is congruent with the guidelines published by EASL.3
If sofosbuvir plus RBV with or without PEG-IFN was used previously, ledipasvir/sofosbuvir with RBV for 12 weeks is recommended in those without cirrhosis while the duration is extended to 24 weeks in the presence of compensated cirrhosis. If an NS3 protease inhibitor (simeprevir, telaprevir, boceprevir) was used previously with PEG-IFN and RBV, then daily fixed-dose combinations of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, daclatasvir plus sofosbuvir or elbasvir/grazoprevir with RBV (at 12 or 16 weeks if baseline NS5A RASs present) are recommended for those with or without compensated cirrhosis.2 Patients who have proved to be particularly difficult to treat are those with genotype 3 who are treatment-experienced and have cirrhosis. Current recommendations for these patients are for sofosbuvir/velpatasvir with weight-based RBV for 12 weeks or daclatasvir plus sofosbuvir with weight-based RBV for 24 weeks. For those with genotype 3 treatment experience who have failed prior sofosbuvir and RBV, whether they have cirrhosis or not, there are less data to support guidance.2
Those failing newer treatments including simeprevir plus sofosbuvir and NS5A inhibitors (daclatasvir, elbasvir, ledipasvir, ombitasvir, velpatasvir) have less formal recommendations. Essentially the AASLD/IDSA guideline recommends testing for NS3 and NS5A RASs, tailoring treatment to the results, and extending dual DAA therapy to 24 weeks with the addition of RBV (if not contraindicated). Triple or quadruple DAA therapy may also be considered.2 In contrast, the EASL guidelines recommend retreatment with a non-IFN regimen with weight-based RBV for 12 weeks with METAVIR fibrosis scores of F0–F2 but for 24 weeks if with F3 fibrosis or cirrhosis.3
For genotype 2 or 3 patients who have previously treated with sofosbuvir plus RBV, daclatasvir plus sofosbuvir with or without RBV for 24 weeks or daily fixed-dose combination sofosbuvir/velpatasvir with RBV for 12 weeks are options. Currently, no formal recommendations exist for the retreatment of DAA failures in those with genotypes 5 or 6.2
EASL guidelines for sofosbuvir failures include retreatment with sofosbuvir/ledipasvir for genotypes 1 and 4–6, sofosbuvir/velpatasvir or sofosbuvir/daclatasvir for all genotypes, ritonavir-boosted paritaprevir with ombitasvir for genotype 4 and the addition of dasabuvir for genotype 1, and sofosbuvir plus simeprevir for genotype 4. If those genotype 1 or 4 patients already failed sofosbuvir plus simeprevir, they can be retreated with a combination of sofosbuvir with ledipasvir, velpatasvir, or daclatasvir. Genotype 1 or 4 patients who have failed NS5A-containing DAA regimens may be retreated with sofosbuvir plus ritonavir-boosted paritaprevir with ombitasvir for genotype 4 or grazoprevir/elbasvir with sofosbuvir for genotypes 1 and 4 or sofosbuvir, simeprevir and daclatasvir for genotypes 1 and 4 for 12 weeks. For those with genotypes 5 or 6 failing an NS5A-containing regimen, the combination of sofosbuvir and velpatasvir with RBV for 24 weeks is recommended.3
Novel regimens expected to be approved in 2017
There are a number of combination regimens currently in phase III development that are expected to be available in 2017. All of these will be pangenotypic, RBV-free and be effective in genotype 1a patients who have failed a DAA regimen containing an NS5A inhibitor. The regimens may be double combinations of very potent pangenotypic protease inhibitors and NS5A inhibitors or triple combinations of protease inhibitors, NS5A inhibitors and NS5b nucleos(t)ide polymerase inhibitors (see Table 1). There are other future regimens beyond these regimens that are anticipated in 2018 or beyond but they are not yet in phase III development so will not be discussed herein.
| GZR + RZV + MK-3682 | RZV + MK-3682 | SOF + VEL + GS-9857 | ABT-493+ABT530 | |
|---|---|---|---|---|
| Manufacturer | Merck (Kenilworth, NJ, USA) | Merck (Kenilworth, NJ, USA) | Gilead (Foster City, CA, USA) | AbbVie (Lake Bluff, IL, USA) |
| Number of drugs | Triplet | Doublet | Triplet | Doublet |
| Drug classes | PI + NS5A + NS5b | NS5A + NS5b | NS5b + NS5A + PI | PI + NS5A |
| Requires RBV? | No | No | No | No |
| Duration of therapy | 4–12 weeks | 4–12 weeks | 12 weeks | 8–12 weeks |
| Genotype efficacy | Pangenotypic | Pangenotypic | Pangenotypic | Pangenotypic |
| DAA-failure with NS5A RASs | Effective, but may require addition of RBV | Effective, but may require addition of RBV | Effective | Effective |
ABT-493, gleaprevir; ABT-530, pibrentasvir; DAA, direct-acting antivirals; GS-9857, voxilaprevir; GZR, grazoprevir; NS5A, NS5A inhibitor; NS5b, NS5b nucleos(t)ide polymerase inhibitor; PI, NS3/4A protease inhibitor; RAS, resistance-associated substitutions; RBV, ribavirin; RZV, ruzasvir; SOF, sofosbuvir; VEL, velpatasvir
Addressing treatment failures is becoming increasingly important in the era of DAA therapy. For genotype 1 infection, the single-pill combination of ledipasvir (NS5A inhibitor) with sofosbuvir (NS5b nucleotide polymerase inhibitor; Harvoni™ Gilead Sciences, Foster City, CA) has shown cure rates >95%.4 According to the Center for Disease Control and Prevention, there are 2.7–3.9 million people in the United States (US) with HCV infection.5 Of these, approximately 75% have genotype 1, highlighting the importance of this patient population sustained virologic response at follow-up week 12.6
Glecaprevir (ABT-493) + pibrentasvir (ABT-530)
Glecaprevir (ABT-493) is a pangenotypic NS3/4A protease inhibitor while pibrentasvir (ABT-530) is a pangenotypic NS5A inhibitor active against common single-position NS5A variants. The two compounds are being developed together in a fixed-dose doublet regimen by AbbVie Pharmaceuticals (Lake Bluff, IL). Different durations of therapy are being evaluated between 6–12 weeks and none of the regimens require RBV. The population being studied does not include decompensated cirrhosis due to the previous experience seen in this group with paritaprevir, telaprevir, simeprevir and other first-generation NS3/4 PIs.7
In the replicon model, the second-generation protease inhibitor glecaprevir showed potent activity against all genotypes with half-maximal effective concentration (EC50) ranging from 0.85–2.8 nm. These numbers are on par or superior to those seen with grazoprevir and paritaprevir. The other drug in the second-generation doublet regimen, pibrentasvir, showed an EC50 range of 1–4 pm across all genotypes, better than other currently available pangenotypic NS5A inhibitors. The SURVEYOR-I study demonstrated 98–100% SVR4 in HCV genotype 1 noncirrhotic treatment-naïve or PEG-IFN/RBV null-responders with the combination of the two drugs.8
The MAGELLAN-I study used a combination of glecaprevir and pibrentasvir to treat those with treatment failures to earlier generation DAAs. The patient population included those with NS3 (30%), NS5A (20%), and both NS3 and NS5A (32%) RASs. Using intention-to-treat (ITT) analysis, for glecaprevir/pibrentasvir at doses of 200 mg/120 mg, the sustained virologic response (SVR) at follow-up week 12 was 100% (n=6). For doses of 300 mg/120 mg, SVR12 was 86% (19/22) and with the addition of RBV 800 mg it was 91% (20/22). Using modified ITT analysis (mITT), those same SVR12s were 100%, 95% and 95%, respectively. Failure was due to both viral breakthrough (n=1) and relapse (n=1).9
The same glecaprevir/pibrentasvir combination was used in a partially randomized, phase II trial for genotype 3 patients with cirrhosis.10 Doses were 200 mg or 300 mg for glecaprevir (30 patients in each group) and 40 mg or 120 mg for pibrentasvir with or without RBV (31 and 30 patients respectively). Again, the study group included those patients with NS3 and NS5A variants either alone or together. By ITT analysis, SVR12 was 93–94% for combination therapy both with and without the addition of RBV.11 The 40 mg arm of pibrentasvir performed less well and will thus not be pursued further.
Sofosbuvir/velpatasvir + voxilaprevir (GS-9857)
The single-pill fixed-dose regimen of sofosbuvir 400 mg and velpatasvir 90 mg is currently approved for all genotypes in the US (Epclusa™; Gilead Sciences, Foster City, CA).12 This regimen must be given for 12 weeks and has not been shown to be effective in patients who have failed NS5A-containing DAA regimens with NS5A RASs. As well, although the compound is approved for decompensated cirrhosis, it must be administered with RBV in this population.12 Gilead Sciences, Foster City, CA, is developing a triplet-combination regimen that would include the addition of a protease inhibitor to sofosbuvir/velpatasvir and offer the possibility of a pangenotypic regimen that would be effective against DAA failures.
This fixed-dose combination of sofosbuvir/velpatasvir was studied in conjunction with voxilaprevir (GS-9857), a pangenotypic NS3/4A protease inhibitor, for DAA-experienced patients with genotype 1. SVR12 for triple therapy was 100% while triple therapy with the addition of RBV had an SVR12 of 96% with overall SVR12 of 98%. Overall, 75% of patients had baseline RASs (NS5A, NS3 or both). Within this group, SVR12 was 97% but 100% for those without any baseline RASs.13
The same drug combination was studied for genotypes 1, 2, 3, 4 and 6. SVR12 was 99% overall and 100% for genotype 1 in treatment-naïve patients with (n = 15) or without cirrhosis (n = 30) and treatment-experienced patients with cirrhosis (n = 17) or polymerase inhibitor-experienced patients with or without cirrhosis (n = 28), 100% for genotype 2, 97% for genotype 3 patients with cirrhosis who were treatment-naïve (n = 18) or treatment-experienced (n = 19), and 100% for genotypes 4 and 6. Those without RASs had an SVR12 of 100% while those with NS3, NS5A or both variants had overall SVR12 of 99%.13-15
MK-3682 + grazoprevir + elbasvir or MK-3682 + grazoprevir + MK-8408
There are two triplet therapies and at least one doublet regimen in development by Merck (Kenilworth, NJ) that include MK-3682 (a novel NS5b nucleotide polymerase inhibitor) with or without grazoprevir and with either elbasvir or MK-8408 (a novel NS5A inhibitor). MK-3682 was tested in 300 mg and 450 mg doses in the CREST 1 (for genotypes 1 and 2) and CREST 2 (for genotype 3) studies. The CREST 1 study showed mITT SVR24 of 91–100% for genotypes 1 (n = 93 with 46 GT1a and 47 GT1b) with either elbasvir or MK-8408 at both doses for MK-3682. However, only the MK-3682 (450 mg)/grazoprevir/MK-8408 regimen showed efficacy >90% in genotype 2 patients (n = 61). For genotype 3 patients, both the 300 mg and 450 mg doses of MK-3682 showed SVR24 rates >90% (n = 86).16,17
Importantly, the presence of genotype 1 NS5A RASs had no effect on SVR12 rates, including those at the 28, 30, 31 and 93 positions. However, none of these patients had failed prior NS5A-containing regimens. Patients were also tested for the presence of pre-existing genotype 1 NS3 and NS5b RASs and these had no effect on SVR12 rates. The same was true in genotype 2 patients however the SVR rates in genotype 3 patients with NS5A RASs were slightly lower than in those without RASs. The tolerability and side-effect profile of these regimens proved to be excellent with essentially no late alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations, and very few serious adverse events. The most common side effects seen in the MK-3682 groups were minimal with headache and fatigue.16
A regimen earlier in development, two of whose three components are currently unapproved, consists of simeprevir, odalasvir (NS5A inhibitor), and ALS-335 (nucleotide polymerase inhibitor). In a recent press release of 20 patients with treatment-naïve genotype 1 treated with the triplet regimen for 8 weeks, 100% achieved SVR24. Additional promising preliminary results were presented for 6 or 8-week regimens as well as an 8-week regimen of the doublet combination of odalasvir (50 mg every other day) and AL-335 (800 mg daily) for 8 weeks. Adverse effects were mild except for a single serious adverse event (Mobitz type 1 second-degree atrioventricular block), which was attributed to treatment.18
MicroRNA-122 inhibition
MicroRNAs regulate messenger RNA levels and translation. Liver-expressed microRNA-122 (miR-122), plays a role in HCV infection of all genotypes by interacting with the HCV RNA genome. Jopling and colleagues19 showed that by sequestering miR-122 in liver cells, the replication of HCV RNA could be diminished. Miravirsen (Santaris Pharma; Copenhagen, Denmark), a locked nucleic acid-modified DNA phosphorothioate antisense oligonucleotide, designed to sequester miR-122 was studied in a phase IIa trial. Although thought to be pangenotypically effective, this trial enrolled only HCV genotype 1 patients (n=36) who received different subcutaneous doses of miravirsen on a weekly basis. Results showed dose-dependent reduction in HCV RNA levels with some durable response. Of note, no viral resistance was noted.20 Another modified oligonucleotide, RG-101, has also been studied in a small trial. A single subcutaneous dose of either 2 or 4 mg/kg was given to 28 total patients. A total of 6 patients in the 2 mg/kg group and 9 patients in the 4 mg/kg group had undetectable levels at 8 weeks while 7 of the 15 responders maintained this at week 20.21 Overall, microRNA-122 targets have shown some promise in small trials however this compound is currently on clinical hold in the US due to Food and Drug Administration concerns about safety. It is unclear what, if any, role these compounds would play in future HCV therapy.
Link Of Interest On This Blog
RG-101
January 31, 2017 Regulus Announces Continuation of RG-101 Clinical Hold - FDA requests longer-term follow-up data from ongoing studies
Conclusion
The value of a single-pill, fixed-dose, RBV-free regimen for all genotypes is obvious as it would obviate the need for genotype and RAS testing prior to treatment and would likely be simple and well tolerated. In addition, the advantage of a shorter duration has been already demonstrated with the use of sofosbuvir/ledipasvir (Harvoni™) in genotype 1 treatment-naïve noncirrhotic patients. The ultimate goal of new regimens will be to remove the complexity of treatment and thus place therapy in the hands of primary care physicians as well as specialists. We think we are well on the road towards this goal and we will likely have multiple drug regimens that afford this simplicity by 2017.
Unresolved issues remain, however, including the cost and access to these drugs and the continued need to evaluate chronic HCV patients for advanced fibrosis or cirrhosis prior to treatment. These patients may be cured with the same regimen however they require assessment for esophageal varices before and after therapy and screening for hepatocellular carcinoma before and at 6 month intervals after successful treatment. Additionally, the safety and efficacy of these fixed-dose regimens will vary in certain populations such as those with end-stage renal disease and decompensated cirrhosis. There will also continue to be drug–drug interactions which preclude their use with other drugs and thus require attention to these details. As such, we think that therapy will remain in the hands of specialists in the near-term but this may change in later years.
Footnotes
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement: Research grants paid to Scripps Health: Gilead, Merck, AbbVie, BMS, HCV Target. Honoraria paid to PJP for Advisory Boards and Speaking/Teaching: Gilead, Merck, AbbVie, Intercept.
Contributor Information
Ara A. Kardashian, Fellow, Division of Gastroenterology/Hepatology, Scripps Clinic, La Jolla, CA, USA.
Paul J. Pockros, Director of Clinical Research, Scripps Translational Science Institute, Scripps Clinic, 10666 N Torrey Pines Rd, La Jolla, CA 92037, USA.
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